delta 8(14)-9, 11-oxido and delta8(14), 9(11)-androstene derivatives



United States Patent A8(14)-9,11-0XIDO AND A8(14)'9(11 -ANDR0STENEDERIVATIVES Eugene J. Agnello and Gerald D. Laubach, Jackson Heights, N.Y., assignors to Chas. Pfizer & Co., Inc., New York, N. Y., acorporation of Delaware No Drawing Application September 4, 1958 SerialNo. 758,917

7 Claims. (Cl. 260-23955) CH3 CH3 CH3 -CH3 /Z Z and the A A and A-dehydro derivatives thereof wherein Z is selected from the groupconsisting of R is selected from the group consisting of hydrogen andacyl hydrocarbon containing up to ten carbon atoms and Alk is selectedfrom the group consisting of alkyl groups containing up to three carbonatoms.

Suitable compounds for the preparation of the valuable compounds of thisinvention include those represented by the formula wherein Z has thesame meaning as above. These compounds can be prepared from the knowncompound A androstene-l1B-hydroxy-3,17-dione in accordance with theprocedure fully described and illustrated in copend- 6 ing andconcurrently filed patent application Serial No. 758,915. Thisapplication describes the preparation of these compounds from thecorresponding 9,8,1lB-oxido- 8(l4)-dihydroandrostene derivatives bytreatment with perchloric acid. The reaction is carried out in analcoholfree hydrocarbon or halogenated hydrocarbon solvent such aspetroleum ether, benzene, chlorobenzene, toluene,

2,877,223 Patented Mar. 10, 1959 ethylene dichloride, chloroform orcarbon tetrachloride at a temperature of from about 0 C. to about 10 C.during a period .of from about 2 to about 25 minutes using at least anequivalent quantity of 60% perchloric acid. vAn excess of perchloricacid as high as 200% can be used to ensure complete reaction.

The desired product is isolated by diluting the reaction mixture Withfrom 1 to 3 times its volume of ice cold water. The resulting aqueousmixture is extracted with a suitable solvent, for example, chloroform ora mixture of chloroform in ethyl acetate. The organic solution is driedover an anhydrous drying agent such as sodium or magnesium sulfate, thedrying agent removed and the desired product isolated by evaporation ofthe solvent, preferably in vacuo. It may be purified by trituration witha 1:1 mixture of ethyl acetate in ether followed byrecrystallization'from ethyl acetate.

The A -compounds of this invention are prepared by dehydration of theabove illustrated l'lfi-hydroxyl compound with, for example,p-toluensulfonic acid in refluxing benzene or preferably with methylsulfonyl chloride in pyridine. In the preferred method, the startingcompound is allowed to stand together with an excess of methyl sulfonylchloride in pyridine at a low temperature, for example, -5 to +5 C. fora period of from about 16 to about 30 hours. The intermediate mesylatecompound can be isolated or alternatively the reaction mixture can berefluxed preferably in an inert atmosphere such as nitrogen for a periodof from about 1 to about 4 hours. The desired compound is isolated byevaporating the solvent in vacuo.

The a -compound of this invention is converted .to a 93,11B-oxide ofthis invention using the procedure of Fried and Sabo as described in theJournal of the American Chemical Society, vol. 79, page 1130. Thecompound is first converted to a bromohydrin using N- bromoacetamide andperchloric acid in peroxide-free dioxane. The bromohydrin, that is, the9a-bromo-l1fihydroxyl compound is converted to a 9,8,11fi-oxide using analkaline reagentsuch as potassium acetate.

In this procedure, the bromohydrin is refluxed for a period of fromabout 30 minutes to about 1 hour in a dioxane-absolute alcohol solutioncontaining from about 500% to about 800% excess .by weight of anhydrouspotassium acetate. At .theend of the reaction period the desired productis p'recipitatedby the addition of water and isolated by filtration. Itis often possible to obtain increased yields of product by concentratingthe filtrate and isolating successive groups of product by filtration.The procedure is fully illustrated in the appended examples.

The above-described bromohydrin is claimed in copending and concurrentlyfiled patent application Serial No. 758,919.

The A -dehydro compound of this invention can be prepared from the abovedescribed compounds by application of the reactions set forth in earlierfiled patent applications Serial No. 526,554, filed August 4, 1955, andSerial No. 633,538, filed January 10, 1957. These applications describedthe method for the introduction of double bonds at the 6(7)-position bydehydrogenation of a 3keto-6-dihydro-A -steroid compound with a v uinonehaving an oxidation-reduction potential less than '0.5 at a temperatureof between 70 C. and C. in an inert organic solvent having a boilingpoint of at least about 70 C. These solvents include mono-nucleararomatic hydrocarbons, mono-nuclear halogenated aromatic hydrocarbonsolvents, oxygenated polar alicyclic organic solvents and oxygenatedpolar aliphatic organic solvents. Typical solvents include tertiarybutanol, n-amyl alcohol, hexanol, isoamyl alcohol, heptanol-3,cyclohexanol,

ortho-dichlorobenzene, xylene, tertiary amyl alcohol,

secondary amyl alcohol, benzene, toluene, acetic acid, propionic acid,butyric acid; butyl acetate, amyl acetate, hexyl acetate, butylpropionate, propyl propionate and amyl propionate. The preparation ofthe valuable compounds of the instant invention using the processdescribed in the earlier filed applications is more fully illustrated inthe appended examples.

Various modifications at the C position can be made by procedures wellknown in the art. For conversion of the l7-keto group to a 17-hydroxygroup the 3-keto group is preferentially converted to a pyrrolidinylderivative, the 17-keto group is then reduced with lithium aluminumhydride and the pyrrolidinyl group removed by refluxing in a sodiumacetate-acetic acid buffered aqueous-methanol solution. This reaction isdescribed in detail by Heyl and Herr in the Journal of the AmericanChemical Society, 75, page 1918 (1953). The vinyl group can beintroduced at the C position by treating the 17-ketone with acetylene inthe presence of a potassium tert-alkoxide (for example, potassiumtert-amyl alkoxide) and reducing the thus produced ethynyl group bycatalytic hydrogenation. For the introduction of the vinyl group the3-keto group should again be protected by a pyrrolidinyl group which is,of course, subsequently removed. The 17-keto group can be converted to atertiary alcohol, that is, an alkyl and hydroxyl group can be introducedat the l7-position by treatment with an organo-metallic compound of thetype RLi or RMgX wherein R is alkyl up to four and X is a halogen. Forthe introduction of the vinyl group or the reaction with anorgano-metallic compound the 3-keto group should be protected by apyrrolidinyl group as described above. A l7-hydroxyl group can bereadily esteritied with the usual esterifying agents if it is thehydroxyl group of a secondary alcohol. If it is the hydroxyl of atertiary alcohol it can be esterified by refluxing in a liquidanhydride, for example, acetic or propionic anhydride or in the case ofa solid anhydride by heating the compound at about 100 C. in ahydrocarbon solvent solution such as xylene containing the anhydride andcatalytic amounts of potassium acetate. Esters and acid esters of the17- hydroxyl group can be obtained in this manner. An 11,8- hydroxylgroup can be converted to a keto group by oxidation, for example, withchromic acid. If, however, there is a secondary hydroxyl group at the17-position, it is best to acylate this group before oxidizing the groupat the ll-position. As stated above, all of these reactions areconventional in the art.

Although the reactions described above are applicable to compounds inwhich the 17-position carries a free 13- hydroxyl group, for optimumresults it is best that this hydroxyl group be acylated with an acylhydrocarbon group containing up to ten carbon atoms. The term acylhydrocarbon includes acyl hydrocarbon groups containing only carbon,hydrogen and oxygen derived from monocarboxylic or dicarboxylic acids.In the event that the acyl hydrocarbon group is one derived from adicarboxylic acid, it is often advantageous to treat the isolatedtherapeutically active compounds with a base derived from an alkalimetal or alkaline earth metal to prepare a metal salt. These basesinclude, for example, sodium, potassium, barium and calcium hydroxide aswell as the corresponding carbonates and bicarbonates. Products soprepared are especially useful because of their increased solubility inwater.

The following examples are given solely for the purpose of illustrationand are not to be construed as limitations of this invention, manyapparent variations of which are possible without departing from thespirit or scope thereof;

EXAMPLE I A (14) 19 -androstatriene-3,1 7 -dione A solution containing 3ml. of pyridine and 0.59 ml.

at a temperature of 0 C. for 24 hours. At the end of this period a smallamount. of ice and water was added and the resulting mixture extractedwith methyl acetate. The organic layer was separated and washedsuccessively with equal volumes of water, 2 N hydrochloric acid andagain with water. It was concentrated to dryness to leave the 118-mesylate as a residue. The residue was dissolved in 3 ml. of pyridineand the solution refluxed in a nitrogen atmosphere for 2 hours. Theresulting solution was extracted with ethyl acetate, the organic layerwashed as described above and the desired product isolated byconcentrating to dryness.

N -androstatetraene-3,17-dione A -androstatetraene-3,l7-dione A-androstapentaene-ii,l7-dione 17u-methyl-A -androstatriene 17 3-ol-3-one17- acetate 7 17a methyl K153091901) androstatetraene 17p ol- 3-one17-acetate 17a methyl A ),9(11) androstatetraene 17p ol- 3-one17-acetate 17oz methyl A androstapentaene 17B- ol-3-one 17-acetate 17ethyl A androstatriene 17B ol 3-one 17-acetate 17a ethylA4"6!8(14),9(11) androstatetraene 17p ol- 3-one 17-acetate 17cc ethyl Aandrostatetraene 1713 o1- 3-one 17-acetate 17 h l .4.6.8(androstapentaene 1713 o1- 3one 17-acetate 17oz propyl A4'8(14)-9(11)androstatriene 17 3 o1 3- one 17-acetate 17a propyl A androstatetraene17p ol- 3-one 17-acetate propyl 1,4,s(1 androstatetraene 17p ol- 3-one17 acetate 17oz propyl A androstapentaene 17pol-3-oue 17-acetate 17ozethynyl A androstatetraene 17p ol- 3-one l7-acetate I ethynyl Aandrostapentaene 17-5- ol-3-one l7-acetate 17o: ethynyl A androstatriene17/3 ol 3- one 17-acetate 17oz ethynyl A androstatetraene 17B o1- 3-one17-acetate 17cc vinyl A androstatriene 17p ol 3- one 17-acetate 17o:vinyl Abfilsuihfln) androstatetraene 17B ol- 3-one 17-acetate 17oz vinylA1'4'8(14),9(11) androstatetraene 17/3 o1 3-oue 17-acetate 17a vinylA1'4618(14)'9(11) androstapentaene 173 o1- 3-one 17-acetate A-androstatrienel7B-ol-3-one 17-acetate A -androstatetraenel7,B-ol-3-one17-acetate A -androstatetraene17,9-ol-3-one 17-acetate A-androstapentaene-l7fi-ol-3-one 17-acetate The above compounds were eachprepared using the procedure of Example 1.

EXAMPLE II 9OL-bI'0mO-A -androstadiene-11 3-018,] 7-dione To asuspension of A -androstatriene-3,17- dione, prepared as described inthe above example, (2.4 g.) in pure peroxide free dioxane (20 m1.) and3.65 ml. of 0.46 N perchloric acid was added in the dark at room"temperature with stirring for a one hour period 1.14 g. ofN-bromoacetamide. At the end of two hours all of the starting materialhad dissolved and 2.5 ml. of sodium sulfite solution was added withstirring. A few grams of ice in 20' ml. of chloroform was added and thelayers separated. The organic layer was washed twice with water whilemaintaining the temperature at about C. by the occasional addition ofice. The organic solution was concentrated in vacuo and triturated inacetone. The mixture was maintained at a temperature of about 5 C. andthe desired product recovered by filtration.

Using this procedure each of the compounds in the list given withExample I were converted to the corresponding 9a-bromo-115-hydroxysteroids.

EXAMPLE III 95-115-0xid0-A -androsladiene-3,1 7-dione A solution of 2.3g. of the compound prepared in the previous example in 75 m1. of dioxanewas added to a solution of 15.8 g. of anhydrous potassium acetate in 160ml. of absolute alcohol at a temperature just below the refluxtemperature of the alcohol solution. The mixture was brought to refluxwithin three minutes and the reaction allowed to proceed for a total offorty minutes. After cooling in an ice bath, 400 ml. of ice water wasadded with stirring and the desired product precipitated. Successivecrops of the desired product were obtained by concentrating the motherliquor.

Using the procedure of this example the following compounds wereprepared.

95,115 oxido A -androstadiene 3,17 dione 95,115 oxido 11 androstatriene3,17 dione 95,115 oxido A androstatriene 3,17- dione 95,115 oxido Aandrostatetraene 3,17 dione 95,115 oxido 17a methyl 175 ol 3 one 17acetate 95,115 oxido 17a methyl M' androstatriene- 175 ol 3 one 17acetate 95,115 oxido 17a methyl A audrostatriene- 175 o1 3 one 17acetate 95,115 oxido 17 methyl A androstatetraene -175 ol 3 one 17acetate 95,115 oxido 17a ethyl A9804) androstadiene- 175 01 3 one 17acetate 95,115 oxido 17a ethyl M androstatriene- 175 o1 3 one 17 acetate95,115 oxido 17oz ethyl A androstatriene- 175 ol 3 one 17 acetate 95,115oxido 17 a: ethyl A androstatetraene- 175 ol 3 one 17 acetate 95,115oxido 17oz propyl A4504) androstadiene- 175 ol 3 one 17 acetate 95,115oxido 17a propyl A androstatriene- 175 o1 3 one 17 acetate 95,115 oxido17cc propyl A androstatriene- 175 ol 3 one 17 acetate 95,115 oxido 17apropyl A androstatetraene -175 -01 3 one 17 acetate 95,115 oxido 17aethynyl A androstadiene- 175 ol 3 one 17 acetate 95,115 oxido 17ccethynyl A androstatriene- 175 ol 3 one 17 acetate 95,115 oxido 17aethynyl 43 androstatriene- 175 ol 3 one 17 acetate 95,115 oxido 17ozethynyl A androstatetraene -175 ol 3 one 17 acetate 95,115 oxido 17o:vinyl A4304) androstadiene- 175 o1 3 one 17 acetate 95,115 oxido 17ozvinyl M51804) androstatriene- 175- 01- 3 -one 17 acetate A 50androstadiene 95,115 oxido 17a vinyl (1 androstatrieneo1 3 one 17acetate 95,115 oxido 17a vinyl A androstatetraene- 175 ol 3 one 17acetate 95,115 oxido A4304) androstadiene 175 o1 3 -one 17 acetate95,115 oxido A androstatriene 175 o1 3 -one 17 acetate 95,115 oxido Aandrostatriene 175 01- 3 -one 17 acetate 95,115 oxido [1androstapentaene 175 ol- 3 one 17 acetate EXAMPLE IV The 17-acetatesprepared as described above are all converted to free alcohols byalkaline hydrolysis using conventional procedures.

EXAMPLE V A variety of 17-esters of the free alcohols prepared asdescribed in the previous examples were each prepared by acylation usingconventional methods. The compounds prepared include formates,propanoates, pro penoates, isobntyrates, hexanoates, benzonoates,octanoates, decanoates, hemisuccinates, trimethyl acetates,cyclopentylpropionates, etc. The acid esters of dicarboxylic acids suchas the hemisuccinate have the advantage that alkali metal salts andalkaline earth metal salts can be prepared from them by treatment withmolar proportions of a base such as sodium or potassium bicarbonate orbarium hydroxide. These salts are water soluble, an advantage notpossessed by the free alcohols themselves or by ordinary esters thereof.

What is claimed is:

1. A compound selected from the group consisting of those having theformulas:

CH; CH1 OH:

and the A A and A -dehydro derivatives thereof wherein Z is selectedfrom the group consisting of No references cited.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULAS: